Association of donor and recipient single-nucleotide polymorphisms of interleukin-1 gene with outcomes after allogeneic hematopoietic stem cell transplantation in childhood

Complications such as graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome, and infections compromise the success of allogeneic hematopoietic stem cell transplantation (HSCT) as a treatment modality for malignant or genetic diseases. Identification of beneficial non-human leukocyte antigens (HLA), such as cytokines, is one approach to reduce the rate of unintended events. This study investigated the association between single-nucleotide polymorphisms (SNPs) of the gene of the proinflammatory cytokine interleukin-1 (IL-1) and treatment outcomes after allogeneic HSCT in a pediatric population.

In our single-center study, we retrospectively analyzed a cohort of 270 children and their respective donors. They underwent allogeneic HSCT for the first time, and their conditioning regimen was myeloablative in all cases. We used polymerase chain reaction to genotype the SNPs of IL-1α rs1800587 (C > T), IL-1β rs16944 (C > T), and IL-1β rs1143627 (C > T). The outcome measures included overall survival (OS), event-free survival (EFS), relapse rate (RR), transplant-related mortality (TRM), and the occurrence of acute or chronic GVHD.

The distribution of IL-1α rs1800587 genotype was as follows: we observed the CC genotype in 124 of 256 recipients (48.4%) and 132 of 270 donors (48.9%). We detected the CT genotype in 115 patients (44.9%) and 114 donors (42.2%) and found the homozygous TT genotype in 17 children (6.6%) and 24 of their donors (8.9%). The distribution of the SNP IL-1α rs1800587 is in Hardy-Weinberg equilibrium. The incidence of moderate or severe acute GVHD was significantly decreased in recipients receiving a donor transplant with the TT genotype (4% (TT) versus 25% (CC/CT); p = 0.028). We found no significant SNP IL-1α rs1800587 (C > T) associations for chronic GVHD, RR, TRM, EFS, and OS. For the other genotypes analyzed, IL-1β rs11644 (C > T) and IL-1β rs1143627 (C > T), we also found no significant associations for acute and chronic GVHD, RR, TRM, EFS, and OS, neither in donors nor in recipients. The results of the multivariate analysis revealed a hazard ratio of 0.17 (confidence interval 0.0229-1.27), and a trend that IL-1α rs1800587 could be an independent risk factor for acute GVHD (p = 0.084).

Our study identified the donor IL-1α rs1800587 CC/CT genotype as a possible genetic risk factor for developing moderate to severe acute GVHD (grade II - IV) in pediatric patients who underwent allogeneic HSCT. Once confirmed in further studies, these results may influence the donor selection and prophylaxis to decrease the risk of acute GVHD in children.